Parasitic protozoa are widely parasitic to animals, such as mammals, fowls, fish, and insects. They mainly parasitize animal internal organs, or skin, eyes, etc., and significantly damage the host, resulting in vast economic loss in domestic animal and poultry and fish industries. Coccidiosis, a parasitic protozoal disease in poultry, is caused mainly by several parasitic protozoa of the genus Eimeria, such as E. tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati. For example, E. tenella parasitizes the walls of the chicken cecum and other intestines to fatally affect the host. Specifically, this infection is manifested as symptoms such as intestinal wall erosion, inflammation and bleeding due to a broad range of intestinal invasion, cecal blood retention, and associated appetite loss and poor growth. Internal parasitic protozoa are generally transmitted orally. In the case of coccidiosis, in particular, oocyst inactivation is impossible even by potent disinfestation with potassium bichromate solution. In addition, because of the generation cycle of as short as about 7 days, there is no effective countermeasure against its rapid infection and onset in large-scale animal breeding.
In the case of fish, protozoa that mainly parasitize external organs are of concern; their parasitization damages the fish skin and gills, and weakens their essential resistance to infectious diseases, which in turn can cause death. In large-scale fish culture, parasitic protozoa spread rapidly over the whole fish in culture, posing a significant problem of economic loss due to such damage.
The same applies to insects. In the case of honeybees, for example, protozoa, such as Nosema apis, have heavily damaged commercial beekeeping all over the world. This parasitic protozoon makes the host less resistant and more susceptible to other diseases, by destroying the host's internal organs.
Traditionally, a large number of chemicals against parasitic protozoa have been known, which, for the most part, are narrow in target and action spectrum, and some have been reported to be ineffective against protozoa that have acquired resistance. In addition, these chemicals are required to be administered at high doses because of their low activity, and are therefore unsatisfactory in terms of economic and environmental aspects. For these reasons, there is strong need for the development of a new chemical that can be widely used with excellent action in the control of parasites in vertebrates, such as mammals, fowls and fish, and insects.
As such drugs, 2-phenyl-6-azauracil derivatives were found to have anti-coccidium action [Journal of Medicinal Chemistry, Vol. 22, p. 1483 (1979)]; various 6-azauracil derivatives were synthesized and investigated but proved to be teratogenic and failed to come into practical application. Later, as nonteratogenic compounds, 2-phenyl-1,2,4-triazinedione compounds, such as a 2-(4-phenoxyphenyl)-1,2,4-triazine derivative [DE-A-2532363] and 2-[4-(1-cyano-1-phenylmethyl)phenyl]-1,2,4-triazine derivative [U.S. Pat. No. 4,631,278), have been developed, some of which have been used to control coccidia in some European countries, Australia, and others but have not been approved for use in Japan, the Unites States and other countries.